RNA therapeutics 2.0: Expanding the landscape from mRNA vaccines to splicing modulators and beyond

RNA therapeutics have progressed into a disruptive drug class quickly, replacing a variety of primary experimental agents which included vaccines, antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), aptamers and RNA editing systems. First-generation modalities, demonstrated by fomivirsen and pegaptanib were limited by vulnerability to nuclease attack, inefficient delivery and immune stimulation were treated with clinical feasibility. Recent clinical achievements, including mRNA vaccinations against COVID-19, have been based on developments in backbone chemistry, nucleoside modifications and targeted delivery including N-acetylgalactosamine (GalNAc) conjugation and lipid nanoparticle (LNP) encapsulation. On this basis, it can be stated that the RNA Therapeutics 2.0 is more stable, tunable and can be targeted to organs and tissues. New methodologies such as circular RNA (circRNAs), self-amplifying mRNAs (saRNAs), splice-switching adenosine specific oligonucleotides (ASOs), small-molecule splicing modulators and adenosine deaminase toward RNA (ADAR)-directed base editors. These new generation systems can be used to make durable protein expression, reversible transcript recoding and precision splicing modulation, extending therapeutic applications to oncology, neurology, metabolic disease and rare genetic disorders. Extrahepatic delivery via innovations in delivery that included ligand-targeted LNPs, peptide conjugates and engineered exosomes is surpassing and artificial intelligence (AI) enhanced design is hastening optimization of RNA sequences, chemistries and vectors. RNA therapeutics in combination with gene therapy can be used to produce personalized therapeutics, such as n-of-1 medicines, based on immune regulation and control circuits. This Review describes the development of early oligonucleotide drugs to a diversified arsenal of RNA platforms, the major advancements, obstacles and emerging technology that characterize the next stage of RNA-based precision medicine.